TW201536745A - 3,4-dihydroisoquinolin-2(1H)-yl compounds - Google Patents

Abstract

The invention provides certain 3,4-dihydroisoquinolin-2(1H)-yl compounds, particularly compounds of formula I, and pharmaceutical compositions thereof. The invention further provides methods of using a compound of formula I to treat cognitive impairment associated with Parkinson's disease or schizophrenia.

Description

3,4-dihydroisoquinoline-2(1H)-based compound

The present invention provides certain 3,4-dihydroisoquinoline-2(1 H )-based compounds, pharmaceutical compositions thereof, methods of use thereof, and processes for their preparation.

Parkinson's disease is characterized by the loss of chronic, progressive neurodegenerative disorders of dopaminergic neurons in the brain. Parkinson's disease presents resting tremors and other motor symptoms (such as lack of exercise and bradykinesia) and non-motor symptoms (such as cognitive impairment, sleep disorders, and depression). Current therapies for treating Parkinson's disease include dopamine precursors (such as levodopa) and dopamine agonists (such as pramipexole). The effectiveness of such direct-acting dopamine therapy is limited, in part due to high dose-related cognitive impairment, risk of seizures (as demonstrated by certain D1 agonists in rodents), and tolerance. There is still a great need for safe and effective treatment of Parkinson's disease.

An allosteric modulator is an agent that remotely alters the interaction of a ligand with its receptor by altering the ligand binding environment. An example of this type of modulation is that the modulator binds to the allosteric (secondary) site and produces a conformational change in the receptor protein that is passed to the ligand (primary) binding site. If the modulator promotes or enhances the interaction of the ligand with the original binding site, the quality of the allosteric effect can be considered positive, or if it inhibits the interaction, the quality of the allosteric effect can be considered negative.

The compound of the invention is a positive allosteric modulator (PAM) of the dopamine 1 receptor (D1). Thus, the compounds of the invention are useful in the treatment of conditions in which D1 exerts a certain effect (eg, Parkinson's disease and schizophrenia), including alleviation of related symptoms (eg, mild cognition in Parkinson's disease) Defects and cognitive impairment and negative symptoms in schizophrenia). It is believed that the compounds of the invention may also be used to treat symptoms of Alzheimer's disease, such as cognitive impairment. The compounds of the invention may also be used to improve motor symptoms in Parkinson's disease as a monotherapy. It is believed that the compounds of the invention are also useful in the treatment of depression and attention deficit hyperactivity disorder (ADHD).

The present invention provides certain novel compounds of PAM as D1 receptors and is thus useful in the treatment of the above conditions. The novel compounds of the invention may provide an alternative treatment for such conditions. The invention additionally provides co-crystallized forms of certain novel compounds.

European Patent Application Publication No. EP 330360 discloses certain isoquinoline compounds which are useful as opioid κ receptor agonists and which are useful as analgesics.

U.S. Patent No. 5,236,934 discloses certain 1,2,3,4-tetrahydroisoquinoline compounds useful as angiotensin II receptor inhibitors and useful in the treatment of CNS disorders, including cognitive dysfunction.

U.S. Patent Application Publication No. US 2006/0287359 discloses certain tetrahydroisoquinoline compounds which are useful as estrogen receptor antagonists and which are useful in the treatment of estrogen-related diseases, including breast cancer.

The present invention provides a compound of formula I:

Wherein n is 0, 1 or 2; R ¹ is halogen; R ² is halogen, H, CN, C1-C3 alkoxy or C1-C3 alkyl; and R ³ is H, halogen, C1-C3 alkoxy Or a C1-C3 alkyl group.

The invention further provides a compound of formula Ia:

Wherein n is 0, 1 or 2; R ¹ is halogen; R ² is halogen, H, CN, C1-C3 alkoxy or C1-C3 alkyl; and R ³ is H, halogen, C1-C3 alkoxy Or a C1-C3 alkyl group.

The invention further provides compounds of formula I or Ia: wherein n is 0, 1 or 2; R ¹ is halogen; R ² is halogen; and R ³ is H or C1-C3 alkoxy.

The invention further provides a compound of formula I or Ia: wherein n is 0, 1 or 2; R ¹ is Cl, F or Br; R ² is Cl, OCH ₃ , H, F, CN or CH ₃ ; and R ³ is OCH ₃ , H, CH ₂ CH ₃ , Cl, OCH(CH ₃ ) ₂ , OCH ₂ CH ₃ , F, CH(CH ₃ ) ₂ or CH ₃ .

The invention further provides a compound of formula I or Ia: n is 0 or 2; R ¹ is Cl; R ² is Cl or F; and R ³ is H or OCH ₃ .

The invention further provides a compound of formula Ib:

Particular compounds of formula I are compounds of formula Ic.

The specific compound of formula I is 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl) 1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone.

The invention further provides a composition comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl Butyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid.

The invention further provides a composition comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5- (in a ratio of about 1:1) 3-Hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid.

The invention further provides a co-crystallized form of a composition comprising: 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3- Hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid.

The invention further provides a stable co-crystal form of a composition comprising: 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3 -Hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid.

The invention further provides a co-crystallized form of a composition comprising: 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3- Hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid, characterized by the use of X of CuKα radiation The ray powder diffraction pattern has a diffraction peak at a 18.2° 2θ diffraction angle and has one or more peaks selected from the group consisting of: 16.0°, 25.4°, and 7.0°; wherein the diffraction angle tolerance is 0.2°.

The specific compound of formula I is 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1 -Methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one.

The present invention further provides 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl a crystalline form of benzyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one characterized by an X-ray powder diffraction pattern using CuKα radiation at a diffraction angle of 14.27° 2θ A peak having a diffraction peak and having one or more groups selected from the group consisting of 15.71°, 18.01°, 18.68°, 22.43°, and 25.08°; wherein the diffraction angle tolerance is 0.2°.

Additionally, the invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient.

Additionally, the invention provides a method of treating Parkinson's disease comprising administering to a patient in need thereof an effective amount of a compound of formula I.

Additionally, the invention provides a method of treating a neurocognitive disorder associated with Parkinson's disease comprising administering to a patient in need thereof an effective amount of a compound of formula I.

Additionally, the invention provides a method of treating schizophrenia comprising administering to a patient in need thereof an effective amount of a compound of formula I.

Additionally, the invention provides a method of treating Alzheimer's disease comprising administering to a patient in need thereof an effective amount of a compound of formula I.

Additionally, the invention provides a compound of formula I for use in therapy.

Additionally, the invention provides a compound of formula I for use as a medicament.

Additionally, the invention provides a compound of formula I for use in the treatment of Parkinson's disease.

Additionally, the invention provides a compound of formula I for use in the treatment of schizophrenia.

Additionally, the invention provides a compound of formula I for use in the treatment of Alzheimer's disease.

Additionally, the invention provides the use of a compound of formula I for the manufacture of a medicament for Parkinson's disease.

Further, the present invention provides a pharmaceutical composition comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3) -Methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid and a pharmaceutically acceptable carrier, diluent or excipient.

The compounds of formula I can be used in combination with other drugs which are useful in the treatment/prevention/repression or amelioration of diseases or conditions useful for the compounds of formula I, including Parkinson's disease and schizophrenia. Thus, such other drugs may be administered simultaneously or sequentially with the compound of formula I in a manner and amount which is conventionally employed. When a compound of formula I is used in combination with one or more other drugs, a pharmaceutical unit dosage form containing such other agents in addition to a compound of formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention comprise one or more other active ingredients in addition to the compounds of formula I. Other examples of active ingredients which are effective in the treatment of Parkinson's disease and which can be administered in combination with a compound of formula I (administered singly or in the same pharmaceutical composition) include, but are not limited to: (a) dopamine precursors, such as levodopa, 甲多多Melevodopa and etilevodopa; and (b) dopamine agonists, including pramipexole, ropinirole, apomorphine, rotigotine, bromine Bromocriptine, cabergoline and pergolide.

It will be understood that the compounds of the invention may exist in stereoisomeric forms. Embodiments of the invention encompass all enantiomers, diastereomers, and mixtures thereof. The preferred embodiment is primarily a diastereomer. More preferred embodiments are primarily one enantiomer.

Preference is given to the specific diastereomers of the compounds of the formula I represented by the compounds of the formula Ia:

Virtual key And wedge Represents the diastereomer of the trans configuration.

By including the compound of Example 1: 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl The example of 1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone represents a more preferred enantiomer of the compound of formula I or Ia.

As used herein, the term "eutectic" refers to a multicomponent crystalline solid form comprising two compounds wherein the compounds are primarily associated via non-covalent and nonionic chemical interactions (eg, hydrogen bonding). In medical technology, a co-crystal typically comprises a first compound (which is an active pharmaceutical ingredient) and a second compound (which is referred to as a guest compound or co-form). The eutectic differs from the crystalline salt form in that the first compound remains substantially unchanged or neutral. The eutectic may differ from the crystalline hydrate or solvate form in that the guest compound is not exclusively water or a solvent. Preferred eutectic systems possess a stable form with a suitable melting point.

As used herein, the group "halogen" means chloro, fluoro, bromo or iodo. The specific meaning of halogen is chlorine and fluorine.

As used herein, the group "C1-C3 alkoxy" is methoxy, ethoxy, n-propoxy and isopropoxy. The specific meaning of the C1-C3 alkoxy group is methoxy.

As used herein, the group "C1-C3 alkyl" means methyl, ethyl or n-propyl. Base and isopropyl. The specific meaning of a C1-C3 alkyl group is a methyl group.

As used herein, the term "patient" refers to an animal (eg, a mammal) and includes a human. Humans are better patients.

It is also recognized that those skilled in the art can treat Parkinson's disease by administering an effective amount of a compound of formula I to a patient currently exhibiting symptoms. Thus, the term "treatment" and "treating" are intended to mean all of the following processes in which the progression of an existing condition and/or its symptoms can be slowed, interrupted, prevented, controlled or stopped, but not necessarily all of the symptoms are completely eliminated.

It is also recognized that those skilled in the art can treat Parkinson's disease by administering an effective amount of a compound of formula I to a patient at risk of future symptoms and intend to include prophylactic treatment of the disease.

As used herein, the term "effective amount" of a compound of formula I refers to a dosage amount effective to treat a condition, such as Parkinson's disease as set forth herein. As a person skilled in the art, the attending diagnosing physician can readily determine the effective amount by using conventional techniques and by observing the results obtained under similar circumstances. In determining an effective amount or dose of a compound of formula I, a number of factors should be considered, including but not limited to: a compound of formula I to be administered; a co-administration of other agents (if used); a mammalian species; its size, age And the general state of health; the extent or severity of the condition (eg, Parkinson's disease); the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of other concomitant agents; Other relevant circumstances.

The compound of formula I can be administered alone or in the form of a pharmaceutical composition containing a pharmaceutically acceptable carrier, diluent or excipient. Such pharmaceutical compositions and their preparation processes are known in the art (see, for example, Remington: The Science and Practice of Pharmacy, edited by D. B. Troy, 21st ed., Lippincott, Williams & Wilkins, 2006).

Positive allosteric modulation analysis of human D1 receptor

The pBABE-bleo vector and the Phoenix retrovirus system were used to generate HEK293 cells stably expressing the human D1 receptor via retroviral gene transduction. The cells were grown in DMEM/F12 (Gibco) supplemented with 10% bovine serum, 20 mM HEPES, 2 mM glutamate and 150 μg/ml zeocin at 37 ° C and 5% CO ₂ . At approximately 80% confluence, cells were harvested using 0.25% trypsin/EDTA, suspended in FBS + 8% DMSO, and stored in liquid nitrogen. On the day of analysis, the cells were thawed and resuspended in STIM buffer (Hanks Balanced Salt Solution supplemented with 0.1% BSA, 20 mM HEPES, 200 μM IBMX and 100 μM ascorbic acid). Test compounds were serially diluted (1:3) in DMSO and then additionally diluted (1:40) into STIM buffer containing 2 x EC ₂₀ concentrations of dopamine. Dopamine The EC ₂₀ is defined as the concentration of cyclic AMP induced increase in dopamine concentration may be up to the maximum amount of 20%; in this assay, EC _max of 5μM, and EC ₂₀ is usually 12nM. 25 μl of this solution was mixed with 25 μl of cell suspension (1,250 cells) and dispensed into each well of a 96-well half-zone plate; the final DMSO concentration was 1.25%. The plates were incubated for 60 min at 25 °C. Use of HTRF detection (Cisbio ^TM) according to the supplier's instructions to quantify cAMP production: lysis buffer containing anti-cAMP cryptate and D2 conjugate (25 l each) was added to each well of the plates incubated for 60-90min and using EnVision plate reader (PerkinElmer ^TM) fluorescence detection. Using cAMP standard curve data is converted into cAMP concentrations, using the four parameter nonlinear logistic equation (Abase ^TM v5.3.1.22) Analysis absolute EC _50. Based on the window between dopamine EC ₂₀ (which defines the minimum response) to the EC _max reaction (defined by the addition of 5 μM dopamine), the absolute EC ₅₀ of the positive allosteric modulator is calculated as the concentration of the half-maximum cAMP .

In the above assay, compounds exemplified herein shows that for the human D1 receptor absolute terms EC ₅₀ of less than 300nM. The compound of Example 1 exhibits D1 receptor in absolute terms for the human EC ₅₀ of 3.66 ± 0.67nM (SEM; n = 9) and a maximum response was 83.8 ± 4.4%. Example 2 of the co-crystal exhibits D1 receptor for human in terms of absolute EC ₅₀ was 1.11 ± 0.11nM (SEM; n = 2). 3 show examples of the compound for the human D1 receptor absolute terms EC ₅₀ was 11.75 ± 1.27nM (SEM; n = 16) and a maximum reaction was 91.3 ± 2.4%. These data show that the compounds of formula I are exemplified as positive allosteric modulators of the human D1 receptor.

The anti-Parkinson effect of the compounds of the invention can be determined using procedures well known in the art (e.g., animal models of autonomous activity), including basal (adaptive) autonomic activity and humanized dopamine 1 receptor (D1) knock-in mice. Resperpine-induced motion inability.

Generation of human D1 receptor knock-in mice

Transgenic mice in which the murine dopamine 1 (D1) receptor is replaced by its human counterpart can be generated by standard techniques. For example, a mouse genomic fragment was subcloned from the RP23 bacterial artificial chromosome library and re-sequenced into a PGK-neo targeting vector. The human D1 receptor open reading frame in exon 2 was used instead of the mouse open reading frame. The neo selection marker downstream of exon 2 is flanked by frt sites for subsequent removal. The flanking of the loxP selection site in exon 2 allows selection of D1 knockout mice by hybridization with mice expressing the cre nuclease gene.

Growth of C57BL/6 N embryonic stem cell line B6- on mitotic inactivated feeder layer of mouse embryonic fibroblasts in high glucose DMEM (20% peptide bovine serum and 2×10 ⁶ units/l leukemia inhibitor) 3. Ten million embryonic stem cells + 30 mg of linearized vector DNA were electroporated and G418 selection (200 mg/ml) was performed. Pure lines were isolated and analyzed by Southern blotting.

The pure lines containing the predicted size inserts were inserted into blastocysts and the resulting mice were genotyped by PCR. The male chimera is crossed with a female containing the Flp nuclease gene to eliminate the selection marker. Progeny containing human D1 receptor and no selection marker were identified by PCR. Male heterozygotes were mated with female C57BL/6 mice. Male and female progeny containing the human D1 receptor were mated and homozygous was identified by PCR. The behavior and reproduction of homozygotes are relatively normal, and the population maintains a homozygous state in the offspring.

Foundation (adaptation) voluntary activity

Autonomous activities were measured using an automated system to track the movement of the mice. Human D1 The gene knock-in mice were placed in the chamber and allowed to acclimate to the chamber for 60 min. During this time, it shows the movement that decreases over time. After administration of the compounds of the invention, animal movement increased in a dose dependent manner.

More specifically, the autonomous activity box is located in a rectangular frame with an infrared beam for measuring athletic activity (horizontal and vertical activity) called walking. Record your own activities between 7:30 and 15:00 hours.

Mice were randomly assigned to treatment groups as shown in Table 1. Each mouse was individually placed in an autonomous cassette for 60 minutes of adaptation. The mice were then orally administered and the total number of walks per mouse was recorded every 10 minutes over a 60 minute period. In the mice pretreated with reserpine, the previous adaptation period was not included. Therefore, the total number of walks was measured immediately after administration for 60 minutes. Transfer the data from the software/computer to the spreadsheet for further analysis. Statistical analysis was performed using one-way ANOVA, followed by post-analysis using Fishers' LSD test or Dunnett's test.

In the basal (adaptive) motion analysis, the compounds of Examples 1, 2, 3, 4 and 13 promoted the movement of mice in a dose-responsive manner (Tables 1 to 5). This analysis shows that the compounds of Examples 1, 2, 3, 4 and 13 are effectively used for the athletic activities of animals adapted to the environment.

Resilience induced by reserpine can not be reversed

Reserpine catecholamine depleting agent (consumption of dopamine and norepinephrine). After 18-24 hours, mice treated with reserpine became unable to exercise and had a reduced autonomous activity count. Evaluation of blood by measuring the effect of compound on autonomic activity approximately 18-24 hours after a single subcutaneous dose of 0.15 mg/kg, 0.3 mg/kg or 0.6 mg/kg reserpine The movement induced by the flat cannot. The equipment used was the same as that used to evaluate the adaptive activities of Example 1 in Tables 6 and 7. For the compound of Example 3 (as shown in Table 8), the Ethovision 8 video tracking system was used to measure autonomous activity.

Male humanized dopamine D1 receptor knock-in mice were randomly assigned to treatment groups. Each mouse was individually placed in an autonomous cassette. The walking of each mouse was measured every 10 minutes after 60 min of administration. Therefore, the effect on the exploratory behavior induced by reserpine was evaluated over a total of 60 minutes. Transfer the data from the software/computer to the spreadsheet for further analysis. Statistical analysis was performed using one-way ANOVA followed by post-analysis using the t-test.

In the above analysis, the compound of Example 1 reversed the effect of reserpine treatment and restored the movement of the mice in a dose-responsive manner, as measured by infrared light beams (Tables 6 and 7). This analysis shows that the compound of Example 1 is effectively used in an in vivo model of Parkinson's disease.

In the above analysis, the compound of Example 3 reversed the effect of reserpine treatment and restored the movement of the mice in a dose-responsive manner, as measured by video tracking (Table 8). This analysis shows that the compound of Example 3 is effectively used in an in vivo model of Parkinson's disease.

Effect of extracellular content of acetylcholine in the prefrontal cortex

Acetylcholine (Ach) is a key neurotransmitter for advanced cognitive function. In Alzheimer's disease, the cortical brain region, which is important for memory function, is degraded, such as cholinergic neurons in the hippocampus. Donepezil (Aricept®) is an acetylcholinesterase inhibitor that increases the brain content of acetylcholine and displays clinical evidence for enhanced cognition. Dopamine D1 agonists have been shown to modulate acetylcholine release and cognitive performance in animal models. It is believed that compounds that increase the extracellular content of Ach in the hippocampus of freely mobilizing humanized dopamine D1 receptor knock-in (hD1KI) mice can be used to treat cognitive dysfunction associated with Alzheimer's disease.

Experimental procedure

The microdialysis probe was stereotactically injected under isoflurane anesthesia into the ventral hippocampus (HPC) of male hD1 KI mice (Charles River, U.K.). The coordinates of the 囟 before probe implantation are: AP-3.1mm; LM+2.8mm; DV-4.5mm.

The next day, animals were ligated to perfuse the probe with artificial CSF containing NaCl (141 mM), KCl (5 mM), MgCl ₂ (0.8 mM), and CaCl ₂ (1.5 mM). After a 90 minute washout period, dialysate samples were collected at 20 minute intervals. After two hours, the animals were orally injected with vehicle (20% hydroxypropyl beta cyclodextrin) or test compound, and the samples were collected for an additional 3 hours. All samples were immediately frozen on dry ice and stored at -80 °C until various neurotransmitters and metabolites were analyzed.

Sample analysis

To each of the dialysis samples (29 μL) was added: 20 μL of buffer (1 M Bis-Tris, pH 10), 20 μL of mixed deuterated standard, and 260 μl of 0.1% w/v tanshinyl chloride (stored in acetone). The sample was vortexed and heated at 65 ° C for 30 min, then dried under N ₂ and resuspended in 40 μl of 50:50 (v/v) ACN:water (containing 10 mM ammonium formate and 0.06% formic acid). The samples were then centrifuged at 13000 rpm and ambient temperature for 10 min and 35 μl were pipetted into 03-FIVR vials; 10 μl was injected onto LC-MS/MS using a CTC PAL HTC-xt autosampler.

Chromatographic separation of tannin samples (including drug standards) was performed using a Shimadzu LC-20AD XR binary pump and a 2.6 μm Phenomenex Kinetex, XB-C18 HPLC column at a gradient. Mobile phase A consisted of 5%: 95% (v/v) acetonitrile/water, 2 mM ammonium formate and 0.06% formic acid, and mobile phase B consisted of 95%: 5% (v/v) acetonitrile/water, 2 mM formic acid. Ammonium and 0.06% formic acid.

AB Sciex API 5500 was operated during the following two periods: Period 1, Positive TIS mode for detection of acetylcholine (Ach), and Period 2, using positive and negative TIS modes.

data processing

Data are expressed as a percentage of the pre-injection period - obtained by averaging three samples (= 100%) prior to drug delivery and expressing each value as a percentage of this value. Statistical analysis was performed using RM/Fit (ANOVA using repeated measures) to compare the responses between treatment groups. A probability value of p < 0.05 can be considered statistically significant.

result

The ACh response was calculated by measuring the area under the curve (AUC) relative to the pre-injection control baseline over a two hour period after drug administration under each drug condition. The data was then analyzed by ANOVA (one-way; JMP v9) followed by an after-the-fact t test.

Administration of the compound of Example 4 (30 mg/kg, intraperitoneal) or the acetylcholinesterase inhibitor dunipici (1 mg/kg, intraperitoneal) was statistically significant compared to the vehicle control. Increase the extracellular content of Ach (Table 9). This shows that the compound of Example 4 is more effective in an in vivo model of Alzheimer's disease.

Table 9

The effect of Example 4 (30 mg/kg, intraperitoneal) or dunipi (1 mg/kg, intraperitoneal) on the ACh response in hippocampus of hD1 KI mice.

The compound of formula I (which comprises a compound of formula Ia, Ib and Ic) can be prepared by processes known in the art or by the novel processes set forth herein. The preparation of the compounds of formula I and the novel intermediates useful in the manufacture of compounds of formula I provides additional features of the invention and is illustrated by the following procedures.

In general, a compound of formula Ia (wherein n is 0, 1 or 2) can be prepared from a compound of formula II wherein n is 0, 1 or 2 and Pg1 represents a suitable hydroxy protecting group (reaction Figure 1). The specific meaning of Pg1 includes a third butyl (dimethyl) decyl group and a tert-butyl (diphenyl) decyl group. More specifically, a compound of formula II wherein Pg1 is a tertiary butyl(dimethyl)decylalkyl group is reacted with a third butyl ammonium fluoride in a solvent such as tetrahydrofuran to provide a compound of formula Ia.

The compound of formula II wherein n is 2 and Pg1 is a tributyl(dimethyl)decyl group can be prepared by reacting a compound of formula III with methyllithium in a suitable solvent (reaction Figure 2). A suitable solvent comprises tetrahydrofuran. By using a compound of formula IV with hydrogen in a suitable transition metal catalyst (eg 1,1'-bis(di-isopropylphosphino)ferrocene (1,5-cyclooctadiene) tetrafluoroborate ( I)) The reaction is carried out in the presence of a compound of formula III wherein Pg1 is a tributyl(dimethyl)decyl group. The reaction is conveniently carried out in a solvent such as methanol. Formula IV can be prepared by reacting a compound of formula V with ethyl acrylate in the presence of a transition metal coupling catalyst (e.g., palladium acetate), a ligand (e.g., tri-o-tolylphosphine), and a base (e.g., triethylamine). a compound (wherein Pg1 is a tributyl(dimethyl)decyl group). The reaction is conveniently carried out in a solvent such as acetonitrile. By using an appropriate R ¹ , R ² , R ³ -phenylacetic acid in an activator (for example, benzotriazol hexafluoro-1-yloxypyrrolidinium hexafluorophosphate) and a base (for example, triethylamine) Deuteration of a compound of formula VIII is carried out in the presence of a compound of formula V. The reaction is conveniently carried out in a solvent such as dimethylformamide.

Alternatively, a compound of formula II can be prepared from a compound of formula VI wherein Pg1 is a suitable hydroxy protecting group (reaction Figure 3). The specific meaning of Pg1 includes a third butyl (dimethyl) decyl group and a tert-butyl (diphenyl) decyl group. More specifically, a compound of formula VI (wherein Pg1 is a tertiary butyl (dimethyl) decyl group) is used in the presence of an activator (for example, 1,1 '-carbonyldiimidazole) using 2,6-dichlorophenylacetic acid. Deuteration is carried out to provide a compound of formula II. The reaction is conveniently carried out in a solvent such as tetrahydrofuran. The compound of formula VI can be prepared by reducing the compound of formula VII using hydrogen in the presence of a catalyst such as palladium. The reaction is conveniently carried out in a solvent such as ethanol. By reacting a compound of the formula VIII with 2-methylbut-3-en-2-ol in a catalyst (for example palladium acetate), a ligand (for example 2-dicyclohexylphosphino-2 ' , 6' -dimethyl The compound of formula VII is prepared by coupling in the presence of a oxybiphenyl) and a base such as potassium carbonate. The reaction is conveniently carried out in a solvent such as dimethylformamide. The compound of formula VIII can be prepared in a multi-step form from a compound of formula X via an intermediate compound of formula IX, as known by chemical techniques or by the procedures described in the Preparations and Examples. The compound of formula X can be prepared as described in the Preparations and Examples.

The compound of formula II wherein n is 0 and Pg1 is a tributyl(dimethyl)decyl group can be prepared by reacting a compound of formula III with methylmagnesium bromide in a suitable solvent (reaction Figure 4). By using an appropriate R ¹ , R ² , R ³ -phenylacetic acid in an activator (for example, benzotriazol hexafluoro-1-yloxypyrrolidinium hexafluorophosphate) and a base (for example, triethylamine) The compound of formula VIIa is subjected to deuteration in the presence of a compound of formula IIIa. The reaction is conveniently carried out in a solvent such as dimethylformamide. The compound of formula VIIa can be prepared by reacting a compound of formula VIII with carbon monoxide and methanol in the presence of a palladium (0) catalyst.

The compound of formula II wherein n is 1 and Pg1 is a tertiary butyl (dimethyl)decyl group can be prepared by reacting a compound of formula IIIb with methylmagnesium chloride in a suitable solvent (reaction Figure 5). By using an appropriate R ¹ , R ² , R ³ -phenylacetic acid in an activator (for example, benzotriazol hexafluoro-1-yloxypyrrolidinium hexafluorophosphate) and a base (for example, triethylamine) Deuteration of a compound of formula VIIb is carried out in the presence of a compound of formula IIIb. The reaction is conveniently carried out in a solvent such as dimethylformamide. Compounds of formula VIIb can be prepared by reacting a compound of formula VIII with acetone in the presence of a palladium (0) catalyst and a ligand as set forth in the Examples and Preparations.

As used herein, "DMSO" means dimethyl hydrazine; "Tris" means hydrazine hydroxymethylamino methane; "DTT" means dithiothreitol; "HEC" means hydroxyethyl fiber. "DMEM" means Dulbecco's Modified Eagle's Medium; "MS" means mass spectrometry; and "HEPS" means 4-(2-hydroxyethyl)-1-hexahydropyridyl Pyrazine sulfonic acid.

Preparation 1

Synthesis of 2-bromo-D-phenylalanine methyl ester hydrochloride.

2-Bromo-D-phenylalanine (22.4 g, 91.8 mmol) was dissolved in methanol (459 mL). At room temperature, hydrazine chloride (65.3 mL, 917.7 mmol) was added. Stir for 36 hours. Concentration under reduced pressure gave the title compound (27.2 g, 92.3 mmol). MS (m/z): 258 (M + 1).

Alternative synthesis of 2-bromo-D-phenylalanine methyl ester hydrochloride.

Acetyl chloride (562.79 g, 7.17 mol) was added to methanol (10.00 L) in a suitable vessel at 0 °C. The mixture was heated to 17.5 ° C and stirred. After 30 minutes, 2-bromo-D-phenylalanine (500.00 g, 2.05 mol) was added and heated to reflux. After 4 hours, the title compound (589 g, 1.96 mol) was obtained. MS (m / z): 258 (M-Cl (79 Br)), 260 (M-Cl (81 Br)).

Preparation 2

Synthesis of methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalanine.

2-Bromo-D-phenylalanine methyl ester hydrochloride (27.2 g, 92.3 mmol) was dissolved in dichloromethane (923 mL) and water Sodium bicarbonate (31.0 g, 369.4 mmol) and methyl chloroformate (7.86 mL, 101.6 mmol) were added at room temperature. The mixture was stirred for 2.5 hours. Dilute with water and extract with dichloromethane. The dichloromethane extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 316 (M + 1).

Alternative synthesis of methyl 2-bromo-N-(methoxycarbonyl)-D-phenylalanine.

Water (2.94 L) and sodium bicarbonate (648.25 g, 7.64 mol) were added to 2-bromo-D-phenylalanine in dichloromethane (9.86 L) at 10 ° C in a suitable vessel. Ester hydrochloride (580 g, 1.91 mol). After 5 minutes, methyl chloroformate (198.53 g, 2.10 mol) was added and the mixture was stirred at 20 °C. After 3 hours, water (2.5 L) was added and the layers were separated. The aqueous solution was extracted with EtOAc (EtOAc)EtOAc. MS (m / z): 315.8 (M + 1 (79 Br)), 317.8 (M + 1 (81 Br)).

Preparation 3

Synthesis of (3R)-5-bromo-3,4-dihydro-1 H -isoquinoline-2,3-dicarboxylic acid dimethyl ester.

2-Bromo-N-(methoxycarbonyl)-D-phenylalanine methyl ester (29.1 g, 92.10 mmol) in glacial acetic acid (115 mL, 2.01 mol) and concentrated sulfuric acid (38.4 mL, 719.9 mmol) A mixture of paraformaldehyde (9.13 g, 101.3 mmol) was stirred at room temperature for 7 hours. It is partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 328 (M + 1).

Preparation 3a

(3R)-5-bromo-3,4-dihydro-1 H -isoquinoline-2,3-dicarboxylic acid dimethyl ester and (3R)-5-bromo-2-methoxycarbonyl-3, Synthesis of 4-dihydro-1 H -isoquinoline-3-carboxylic acid.

Add 2-bromo-N-(methoxycarbonyl)-D-phenylalaninate (572 g, 1.81 mol) and paraformaldehyde (205.86 g) to acetic acid (4.29 L) at 10 ° C in a suitable vessel. , 2.17mol). After 10 minutes, concentrated sulfuric acid (2.63 kg, 26.83 mol) was slowly added and then stirred at 35 °C. After 12 hours, it was cooled to 15 ° C and water (7.5 L) and ethyl acetate (6 L) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2.5L). The combined organic extracts were dried with EtOAc (EtOAc m. Mass spectrum (m / z): 3a: 327.95 (M + 1 (79 Br)), 330.05 (M + 1 (81 Br)). 3b: 314 (M+1 ( ⁷⁹ Br)), 315.95 (M+1 ( ⁸¹ Br)).

Preparation 4

Synthesis of (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride.

(3R)-5-Bromo-3,4-dihydro-1 H -isoquinoline-2,3-dicarboxylic acid dimethyl ester (27.55 g, 84.0 mmol) was dissolved in 5N hydrochloric acid (330.6 mL, 1.65 mol) ) and heated to reflux for three days. Concentration under reduced pressure gave a white solid. The solid was washed with diethyl ether and dried under vacuum at 40 ° C overnight to give (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1:1) (20.8 g, 71.1 mmol). Acetyl chloride (50.6 mL, 711.0 mmol) was added to (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride in methanol (474 mL). (1:1) (20.8 g, 71.1 mmol) in a 0 ° C mixture. The temperature was raised to room temperature and stirred for 36 hours. Concentration under reduced pressure and dried MS (m/z): 270 (M + 1).

Preparation 5

Synthesis of (3R)-5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride.

Add water (1.3 L) and 36.5% hydrochloric acid (9.07 Kg, 90.81 mol) to the (3R)-5-bromo-3,4-dihydro-1 H -isoquinoline-2,3 in a suitable vessel. - dimethyl dicarboxylate and (3R)-5-bromo-2-methoxycarbonyl-3,4-dihydro-1 H -isoquinoline-3-carboxylic acid (Preparation 3a) (520 g, 1.27 mol) The mixture was stirred at 95 ° C. After 12 hours, the mixture was cooled to 10 ° C and stirred for 15 minutes. The mixture was filtered and dried <RTI ID=0.0> MS (m / z): 256.1 (M-Cl (79 Br)), 258 (M-Cl (81 Br)).

Preparation 6

Synthesis of 2-tert-butyl-3-methyl-(3R)-5-bromo-3,4-dihydro-1 H -isoquinoline-2,3-dicarboxylate.

(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (21.0 g, 68.5 mmol) was dissolved in 1,4-dioxin (685 mL) in. A saturated sodium bicarbonate solution (685 mL, 17.5 mol) and di-tert-butyl dicarbonate (29.9 g, 137.0 mmol) were added at room temperature. The biphasic mixture was stirred for 90 min. Extract with ethyl acetate. The ethyl acetate was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 270 (M-tBOC +1).

Preparation 7

Synthesis of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol.

Add lithium aluminum hydride (2 L, 2.00 mol, 1 M in THF) to (3R)-5-bromo-1,2 in tetrahydrofuran (4.88 L) at -35 °C. 3,4-Tetrahydroisoquinoline-3-carboxylic acid hydrochloride (325.4 g, 1.11 mol) was then warmed to 25 ° C over 60 min and stirred. After 3 hours, the mixture was cooled to -5 ° C then water (76 mL), 15% w/w aqueous sodium hydroxide (76 mL) and water (228 mL). The mixture was heated to 25 ° C, anhydrous magnesium sulfate (750 g) was added and stirred. The mixture was filtered and concentrated under reduced pressure to give a solid. Dichloromethane (690 mL) was added to the solid and slurried over 30 min then filtered to give a solid. The solid was dried under vacuum <RTI ID=0.0></RTI> to <RTI ID=0.0> MS (m / z): 242 (M + 1 (79 Br)), 244 (M + 1 (81 Br)).

Preparation 8

Synthesis of (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1 H -isoquinoline-2-carboxylic acid tert-butyl ester.

Methanol (10.1 mL, 248.5 mmol) and lithium borohydride (99.4 mL, 198.8 mmol, 2 M in THF) were added to a mixture of 2-tert. in tetrahydrofuran (497 mL). A solution of benzyl-3-methyl-(3R)-5-bromo-3,4-dihydro-1 H -isoquinoline-2,3-dicarboxylate (18.4 g, 49.7 mmol). Stir for 40 min and stop the reaction with water. Extract with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc EtOAc:EtOAc) The title compound (19.1 g, 55.8 mmol) was obtained. MS (m/z): 286 (M-tBu+1).

Preparation 9

Synthesis of (3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1,2,3,4-tetrahydroisoquinoline.

Trifluoroacetic acid (75.5 mL, 998.3 mmol) was added to (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro in dichloromethane (226 mL) at rt. -1 H -Isoquinoline-2-carboxylic acid tert-butyl ester (15.5 g, 45.3 mmol) in a solution. Stir for 30 min and concentrate under reduced pressure. Drying under vacuum to give [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol as a wet solid; 2,2,2-trifluoroacetic acid. [(3R)-5-Bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol; 2,2,2-trifluoroacetic acid was dissolved in dichloromethane (753 mL). 1 H -Imidazole (51.3 g, 753 mmol), N , N -dimethyl-4-aminopyridine (460 mg, 3.77 mmol) and tert-butyldimethylchloromethane (13.6 g, 90.4 mmol) were added. Stir at room temperature overnight. A saturated ammonium chloride solution was added and extracted with dichloromethane. The dichloromethane extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. Substantially identical to the reaction from the use of 19.4 mmol of (3R)-5-bromo-3-(hydroxymethyl)-3,4-dihydro-1 H -isoquinoline-2-carboxylic acid tert-butyl ester The crude product was combined. The residue was purified with EtOAc EtOAcjjjjjj MS (m/z): 356 (M + 1).

Alternative synthesis of (3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1,2,3,4-tetrahydroisoquinoline.

Addition of tert-butyldimethylchloromethane (193.7 g, 1.29 mol) to [(3R)-5-bromo-1,2,3 in dichloromethane (2.61 L) at 20 °C 4-tetrahydroisoquinolin-3-yl]methanol (148.9 g, 0.58 mol), 1 H -imidazole (202.9 g, 2.92 mol), 4-dimethylaminopyridine (0.72 g, 5.84 mmol) and N , a mixture of N-dimethylformamide (1.04 L) and stirred in a suitable vessel. After 3 hours, the mixture was cooled to 10 ° C and saturated aqueous ammonium chloride (1.3 L) was added. The combined organic extracts were washed with brine (2×2 L), dried over anhydrous sodium sulfate and evaporated The residue was dissolved in methyl tert-butyl ether (1.5 L) and washed with brine (2×1L). The organic phase was diluted with toluene (5 L) and concentrated under reduced pressure to give a residue. To the residue was added toluene (2.6 L). MS (m / z) .356 ( M + 1 (79 Br)), 358 (M + 1 (81 Br)).

Preparation 10

Synthesis of (3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-3,4 dihydroisoquinoline.

(3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1,2,3,4-tetrahydroisoquinoline (4.2 g, 11.8 mmol) was dissolved in diethyl ether (118 mL). N-chlorosuccinimide (2.36 g, 17.7 mmol) was added. Stir at room temperature for 30 min and concentrate under reduced pressure. The residue was dissolved in potassium hydroxide (42.0 mL,EtOAc. Pour into water and extract with dichloromethane. The dichloromethane extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjj MS (m/z): 354 (M + 1).

Alternative synthesis of (3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-3,4 dihydroisoquinoline.

Add N-chlorosuccinimide (106.7 g, 0.79 mol) to the (3R)-5-bromo-3- ({[third) in tetrahydrofuran (3.85 L) at 20 ° C in a suitable vessel. A solution of butyl(dimethyl)decyl]oxy}methyl)-1,2,3,4-tetrahydroisoquinoline (220 g, 0.52 mol) was stirred. After 30 minutes, the mixture was concentrated under reduced pressure and the residue was evaporated mjjjjjjjjjjjj After 30 minutes, the mixture was added to water (3 L) and extracted three times with dichloromethane (3×1L). The combined organic extracts were dried with EtOAcjjjjjjjj MS (m / z): 354 (M + 1 (79 Br)), 356 (M + 1 (81 Br)).

Preparation 11

(1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-1,2,3,4-tetrahydroiso Synthesis of quinoline.

Dissolving (3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-3,4 dihydroisoquinoline (3.4 g, 9.59 mmol) In diethyl ether (160 mL). Cool to -78 ° C in an anhydrous ice-acetone bath. Methylmagnesium chloride (26.9 mL, 80.6 mmol, 3 M in THF) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. Slowly quench using a saturated ammonium chloride solution. It was extracted with dichloromethane and dried over sodium sulfate, filtered and evaporated. Substantially identical reaction from the use of 1.73 mmol(3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-3,4 dihydroisoquinoline The crude products of the test were combined. The combined residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 370 (M + 1).

The compound (1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)- was determined by NMR spectroscopy using a one-dimensional NOE experiment (1D-NOESY). The relative configuration of 1-methyl-1,2,3,4-tetrahydroisoquinoline. The methyl group at 1.30 ppm was selectively excited to give a Ha NOE at 3.11 ppm. This NOE enhancement is consistent only with the configuration of the methyl and Ha on the same side of the ring (trans isomer) because the methyl protons in the cis isomer are too far away from Ha to exhibit NOE. Since the absolute chemistry of the three positions is known to be R, it is estimated that the absolute chemistry of the one position is S.

(1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-1,2,3,4-tetrahydroiso Alternative synthesis of quinoline.

Methylmagnesium chloride (0.66 L, 1.99 mol, 3 M in THF) was added to the (3R)-5-bromo-3-(2) in diethyl ether (2.8 L) at -65 °C. A solution of {[t-butyl(dimethyl)decyl]oxy}methyl)-3,4 dihydroisoquinoline (93.5 g, 0.24 mol). The reaction mixture was then heated to 20 ° C over 2 hours and stirred. After 16 hours, the mixture was cooled to 0 ° C and quenched with saturated aqueous ammonium chloride (2.5L) and ethyl acetate (2.5L) The combined organic extracts were washed with EtOAcqqqqqm The oil was substantially separated from the use of 48 mmol and 229 mmol of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-decane. The crude product of the same reaction was combined and purified by chromatography eluting eluting eluting eluting elut . MS (m / z): 370.1 (M + 1 (79 Br)), 372.1 (M + 1 (81 Br)).

Preparation 12

(1S,3R)-5-bromo-3-[[t-butyl(dimethyl)decyl]oxymethyl]-1-methyl-3,4-dihydro-1H-isoquinoline- Synthesis of 2-butylic acid tert-butyl ester.

Di-tert-butyl dicarbonate (1.23 g, 5.54 mmol) was added to [(1S,3R)-5-bromo-1-methyl-1,2,3 in dichloromethane (15 mL) , a solution of 4-tetrahydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-decane (2.01 g, 5.43 mmol). The reaction mixture is in the ring Stir at ambient temperature overnight. Concentrate under reduced pressure. The residue was taken up in EtOAc (EtOAc)EtOAc. Purify by silica gel chromatography eluting EtOAc (EtOAc:EtOAc MS (m/z): 370.2, 372.2 (M-BOC +1).

Preparation 13

1-[(1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-3,4-dihydroisoquine Synthesis of porphyrin-2(1 H )-yl]-2-(2,6-dichlorophenyl)ethanone.

Addition of benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (7.97 g, 15.3 mmol) to (1S,3R)-5 in dimethylformamide (51.0 mL) -Bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (3.78 g, 10.2 Methyl) and a mixture of 2,6-dichlorophenylacetic acid (2.30 g, 11.2 mmol). Triethylamine (2.13 mL, 15.3 mmol) was added and stirred at room temperature for 3 h. Dilute with water and extract with dichloromethane. The dichloromethane extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 556 (M + 1).

Preparation 14

(2E)-3-{(1S,3R)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-2-[(2,6-dichlorophenyl) Synthesis of ethyl keto]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}prop-2-enoate.

Nitrogen was bubbled through acetonitrile. Tri-o-tolylphosphine (72.3 mg, 0.23 mmol), palladium (II) acetate (11.8 mg, 0.052 mmol) and acetonitrile (0.96 mL) were placed in a microwave vessel. Stir for 10 min. Ethyl acrylate (0.31 mL, 2.88 mmol) was added. Add 1-[(1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-3,4-dihydroiso) Quinoline-2(1 H )-yl]-2-(2,6-dichlorophenyl)ethanone (0.54 g, 0.96 mmol). Triethylamine (0.40 mL, 2.88 mmol) was added and stirred vigorously. Nitrogen is blown through the surface of the reaction liquid. The vessel was sealed and heated to 160 ° C in the microwave for 35 min. Cool to room temperature and dilute with ethyl acetate. The precipitate was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give a brown oil. With from the use of 0.27mmol 1-[(1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-3,4 - The crude product of the substantially identical reaction test of dihydroisoquinoline-2( 1H )-yl]-2-(2,6-dichlorophenyl)ethanone was combined. The combined residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 576 (M + 1).

The following compounds were prepared essentially by the method of Preparation 14.

Preparation 16

(1S,3R)-3-[[T-butyl(dimethyl)decyl]oxymethyl]-5-(3-ethoxy-3-oxirane-propyl)-1-methyl Synthesis of tert-butyl 3-, 4-dihydro-1H-isoquinoline-2-carboxylate.

10% palladium on carbon (0.09 g) was added to a 100 ml Parr bottle. Use a nitrogen purge. Ethanol (5 mL) was added to wet the catalyst. Add (1S,3R)-3-[[t-butyl(dimethyl)decyl]oxymethyl]-5-[(E)-3-ethoxy-] in ethanol (15 mL) A solution of 3-tert-oxy-prop-1-enyl]-1-methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (330 mg, 0.67 mmol). Seal the bottle and purge with nitrogen. A hydrogen purge vessel was used and pressurized to 414 kPa of hydrogen. Shake for 1.5 hours at room temperature. Vent and open the vessel. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 392.2 (M-BOC +1).

Preparation 17

3-{(1S,3R)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-2-[(2,6-dichlorophenyl)ethenyl] Synthesis of ethyl 1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}propanoate.

In a dry box, add 1,1'-bis(di-isopropylphosphino)ferrocene (1,5-cyclooctane) to a 85 ml Parr autoclave with a stir bar and glass lining. Ethylene tetrafluoroboron Strontium (I) (7 mg, 0.010 mmol). Add (2E)-3-{(1S,3R)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-2-[] in anhydrous methanol (5 mL) (2,6-Dichlorophenyl)ethinyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl}prop-2-enoic acid ethyl ester (133 mg, 0.23 A solution of mmol). The autoclave was sealed and taken out of the drying oven. A hydrogen purge vessel was used and pressurized to 690 kPa of hydrogen. Stir at room temperature overnight. Vent and open the vessel. The reaction mixture was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjj MS (m/z): 578 (M + 1).

Preparation 18

(1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-1,2,3,4-tetrahydroiso Synthesis of quinoline hydrochloride.

Hydrogen chloride (267.24 g, 1.02 mol, 4 M in 1,4-dioxin) was added to (1S,3R)-5- in isopropyl acetate (4.19 L) at 10 °C. Bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline (419 g, 1.02 mol) Stir in a suitable vessel for 15 minutes. The mixture was filtered and the filter cake was washed with EtOAc (EtOAc) (EtOAc). MS (m / z): 370 (M-Cl (79 Br)), 372 (M-Cl (81 Br)).

Preparation 19

(E)-4-[(1S,3R)-3-[[T-butyl(dimethyl)decyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydro Synthesis of isoquinolin-5-yl]-2-methyl-but-3-en-2-ol.

In a suitable vessel, (1S,3R)-5-bromo-3-({[t-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-1,2,3 , 4-tetrahydroisoquinoline hydrochloride (310 g, 723.83 mmol) and 2-methylbut-3-en-2-ol (508.95 g, 5.79 mol) were added to N,N-dimethylformamide (1.08 L) was degassed by bubbling nitrogen through the solution for 10 minutes. Potassium carbonate (315.12g, 2.28mol), 2- dicyclohexylphosphino-2 ', 6' - dimethoxy biphenyl (15.32g, 36.19mmol) and palladium acetate (II) (8.29g, 36.19mmol And degassing by bubbling nitrogen through the mixture for 15 minutes and then heating to 125 °C. After 16 hours, the mixture was cooled to 20 ° C and diluted with ethyl acetate (1.5 L) and water (2.5L). The ethyl acetate layer was washed with brine (2.5 L), then dried over sodium sulfate and evaporated The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 376 (M + 1).

Preparation 20

4-[(1S,3R)-3-[[T-butyl(dimethyl)decyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline- Synthesis of 5-yl]-2-methyl-butan-2-ol.

(E)-4-[(1S,3R)-3-[[T-butyl(dimethyl)decyl]oxymethyl]-1-methyl-1 in ethanol (816 mL) , a solution of 2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-but-3-en-2-ol (68 g, 168.83 mmol) was added to a pressure hydrogenation vessel and added 5% Palladium on activated carbon (35.83 g, 16.84 mmol). Use a hydrogen purge vessel to pressurize to 470 kPa of hydrogen and Stir at 25 °C. After 16 hours, the vessel was vented and the reaction mixture was filtered through celite. The diatomaceous earth was washed with ethyl acetate and the filtrate was concentrated under reduced pressure to give an oil. The oil was dissolved in EtOAc (EtOAc)EtOAc. MS (m/z): 378.2 (M + 1).

Preparation 21

1-[(1S,3R)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1- Synthesis of methyl-3,4-dihydroisoquinolin-2(1 H )-yl]-2-(2,6-dichlorophenyl)ethanone.

4-[(1S,3R)-3-[[Terbutyl(dimethyl)decyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline 5-5-yl]-2-methyl-butan-2-ol (0.21 g, 0.36 mmol) was dissolved in THF (2.0 mL). Cool in a dry ice-acetone bath. Methyl lithium (0.67 mL, 1.07 mmol, 1.6 M in diethyl ether) was slowly added and stirred in a dry ice-acetone bath for 4 h. Saturated ammonium chloride solution (2 mL) was added. The dry ice-acetone bath was removed and the mixture was allowed to warm to room temperature. Extract with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfates The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 564 (M + 1).

1-[(1S,3R)-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1- Alternative synthesis of methyl-3,4-dihydroisoquinolin-2(1 H )-yl]-2-(2,6-dichlorophenyl)ethanone.

In a suitable vessel, 1,1 '-carbonyldiimidazole (112.9 g, 682.36 mmol) was added to a mixture of 2,6-dichlorophenylacetic acid (173.09 g, 818.83 mmol) in tetrahydrofuran (1.63 L). It was stirred at 25 ° C. After 1 hour, 4-[(1S,3R)-3-[[t-butyl(dimethyl)decyl]oxymethyl]-1 was added to the mixture in tetrahydrofuran (1.63 L). a solution of methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (217 g, 545.89 mmol), which was heated to 45 ° C and Stir. After 24 hours, the mixture was cooled to 20 ° C, 2 L of tetrahydrofuran was removed by concentration under reduced pressure, and the residue was diluted with ethyl acetate (2.5 L). The ethyl acetate solution was washed with a saturated aqueous solution of ammonium chloride (1.5 L), 1M aqueous sodium hydroxide (1 L), water (1L) and brine (l.L). The title compound (376 g, 532.70 mmol) was obtained. MS (m / z): 564.2 (M + 1 (35 Cl)), 566.2 (M + 1 (37 Cl)).

The following compounds were basically prepared by the method of Preparation 21.

Example 1

2-(2,6-Dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl- Synthesis of 3,4-dihydroisoquinolin-2(1 H )-yl]ethanone.

1-[(1S,3R)-3-({[Tertibutyl(dimethyl)decyl)oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1 -Methyl-3,4-dihydroisoquinolin-2(1 H )-yl]-2-(2,6-dichlorophenyl)ethanone (0.16 g, 0.28 mmol) dissolved in THF (2.8 mL )in. Tetrabutylammonium fluoride (0.30 mL, 0.30 mmol, 1 M in THF) was added. Stir for 40 min. A saturated ammonium chloride solution was added and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 450 (M + 1).

2-(2,6-Dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl- Alternative synthesis of 3,4-dihydroisoquinolin-2(1 H )-yl]ethanone.

Add 4-(n-butylammonium fluoride) (651.71 mL, 651.71 mmol, 1 M in THF) to 1-[(1S,3R) in tetrahydrofuran (4L) in a suitable vessel at 5 °C. -3-[[Third butyl(dimethyl)decyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydro A solution of isoquinoline-2(1 H )-yl]-2-(2,6-dichlorophenyl)ethanone (400 g, 566.71 mmol). The mixture was heated to 20 ° C and stirred. After 3 hours, 3 L of tetrahydrofuran was removed by concentration under reduced pressure and the residue was diluted with ethyl acetate (2.5L). The organics were washed with a saturated aqueous solution of ammonium chloride (2 L), water (2L) and brine (2×2L). The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. This oil was dissolved in 2-propanol (2.5 L). By using a palmitic SFC (using an AS-H column (50 x 250 mm, 5 micron particle size), using 80% supercritical carbon dioxide and 20% 0.2% diethylmethylamine solution in isopropanol Purification by 280 g/min. to give the title compound (182.8 g, 389.62 mmol). MS (m / z): 450.2 (M + 1 (35 Cl)), 452.2 (M + 1 (37 Cl)). Optical rotation: [α] ²⁰ _D -39.4° (c = 0.95, MeOH).

Example 2

2-(2,6-Dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl- Co-crystallized from 3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid.

The compound 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl The base-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone (402.56 mg) and 4-hydroxybenzoic acid (144.7 mg) were placed in a 40 mL vial with a stir bar. Fill the vial with water (39 mL). The sample was stirred at 1200 rpm and 50 ° C (stirring plate setting). The eucalyptus oil is added dropwise to the base of the vial to ensure good heat transfer with the hot plate. As a result, a thick white slurry having an agglomerate of an off-white solid was obtained. One hour after the slurry was formed, the thermometer inserted into the vial septum read 40.5 ° C and the sample turned into a homogenous slurry of bright white solids. After the slurry was allowed to stand overnight, the sample was a homogenous slurry of a flocculent white solid. The thermometer reads 43.1 °C. Polarized light microscopy shows complete birefringence. The bright white solid was separated by vacuum filtration and dried under air flow for 10 minutes in place. The sample was placed in a vacuum oven at 75 ° C for two hours to provide the title composition (484 mg, yield 94.9%) as a white crystalline solid.

Initial melting point = 160.0 ° C (differential scanning calorimetry).

X-ray powder diffraction

An X-ray diffraction (XRD) pattern of crystalline solids was obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa source (λ = 1.54060 Å) and a Vantec detector operating at 35 kV and 50 mA. The sample was scanned between 4° and 40° 2θ with a step size of 0.009° 2θ and a scan rate of 0.5 sec/step, and a 0.6 mm divergence slit, 5.28 fixed anti-scatter slit and 9.5 mm detector slit were used. . The dry powder was stacked on a quartz sample holder and a smooth surface was obtained using a glass slide. The crystal form diffraction pattern is collected at ambient temperature and relative humidity. It is well known in the art of crystallography that for any given crystal form, the relative intensity of the diffraction peaks may be due to better orientation resulting from factors such as crystal morphology or habit. And change. In the presence of a better orientation, the peak intensity will change, but the characteristic peak position of the polymorph will not change. In addition, it is also well known in the field of crystallography that the peak angular position may vary slightly for any given crystal form. For example, the peak position may be shifted due to changes in temperature or humidity at the time of analysis of the sample, displacement of the sample, or presence or absence of an internal standard. In this case, the peak positional variability of 0.2 2θ will take into account such potential changes, which does not prevent a clear identification of the specified crystal form. The confirmation of the crystal form can be carried out based on any unique combination of distinct peaks (usually more prominent peaks, in units of ° 2θ). (United States Pharmacopeia, 35, National Formulary, Chapter <941>, pp. 427-432, 2012). The crystal form diffraction pattern collected at ambient temperature and relative humidity is adjusted according to the NIST standard reference material 675 (mica) having peaks at 8.853 and 26.774 degrees 22.

The prepared sample of the eutectic of Example 2 is characterized in that its X-ray diffraction pattern (using CuKa radiation) has a diffraction peak (2θ value) as set forth in Table 3 below, and specifically has a peak of 18.2 and one or A plurality of peaks selected from the group consisting of: 16.0 peaks, 25.4 peaks, and 7.0 peaks; wherein the diffraction angle tolerance is 0.2°.

2-(2,6-Dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl- Alternative preparation of co-crystals of 3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid.

Add 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)- to a 20 mL vial 1-Methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone (2.00 g, 1.00 eq; 4.44 mmol). Acetone (4 mL) was added while stirring at room temperature. A clear solution is formed. 4-Hydroxybenzoic acid (0.756 g; 1.23 equivalent; 5.47 mmol) was added while stirring at room temperature. A dilute suspension is formed which then forms a thick suspension. The mixture was heated to 60 ° C on a hot plate. A 1 mL aliquot of acetone was added until a well mixed suspension was observed at 60 °C. The total acetone added was 9.00 mL (122.43 mmol, 7.11 g). The temperature was maintained at about 60 ° C for several hours. The mixture was cooled to room temperature and placed in a refrigerator to improve recovery. The resulting solid was collected by vacuum filtration, washed with 2 mL of acetone and dried in vacuo oven overnight at 40 &lt;0&gt;C to afford the title compound as a white crystalline solid.

HPLC analysis showed 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl) in the cocrystal The molar ratio of 1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone to 4-hydroxybenzoic acid was 1:1.

HPLC analysis

Column: Agilent ZORBAX Bonus-RP, Rapid Resolution, 4.6×75mm, 3.5μ

Column temperature: 30 ° C

Injection volume: 2μL

Detection: UV

2-(2,6-Dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl- 3,4-Dihydroisoquinoline-2(1 H )-yl]ethanone (Example 1) at 219 nm

4-hydroxybenzoic acid at 256 nm

Flow rate: 1.5 mL/min.

Mobile phase: A) 0.1% TFA in water

B) 0.1% TFA in acetonitrile

Gradient table

Relative ratio

2-(2,6-Dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl- A second alternative preparation of a co-crystal of 3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid.

The compound 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl 3-3,4-Dihydroisoquinolin-2(1 H )-yl]ethanone (45.06 g, 0.1 mol) and 4-hydroxybenzoic acid (14.5 g, 1.05 mol equivalent) at 23 ° C at 53: A slurry of 47 isopropanol: heptane (236 mL, 4 volumes) was prepared and heated to 65 °C. Using 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl a co-crystal of 3,4-dihydroisoquinoline-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid (553 mg, 1.0 wt.% seed loading) seeded the resulting solution and Stir at 65 ° C for 30 minutes. Heptane (943 mL, 16 volumes ³ ) was added over 4.6 hours at 65 °C. The slurry was stirred at 65 ° C for an additional 30 minutes, cooled to 23 ° C over 2 hours, stirred at 23 ° C overnight and filtered under vacuum. The product solid was washed with 10:90 isopropanol: heptane (2 x 50 mL) and heptane (50 mL) and then dried in vacuo oven at 40 &lt;0&gt;C for 2h to give the title compound as a white crystalline product (51.3 g The yield was 86.3 wt%).

Initial melting point = 162.2 ° C (differential scanning calorimetry).

Preparation 23

4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butane-2 - Synthesis of alkanoic acid hydrochloride.

(1S,3R)-3-[[Terbutyl(dimethyl)decyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl- 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (161 mg, 0.34 mmol) was dissolved in ethyl acetate (962L). Cool in an ice bath. Hydrogen chloride (843 μL, 3.37 mmol, 4 M in dioxane) was added and stirred in an ice bath for 4 hours. Concentrate under reduced pressure. This was dissolved in ethanol and concentrated under reduced pressure toiel MS (m/z): 264.2 (M + 1).

The following compounds were basically prepared by the method of Preparation 23.

Preparation 25

1-[(1S,3R)-3-[[T-butyl(dimethyl)decyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl Synthesis of benzyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-chloro-5-methoxy-phenyl)ethanone.

4-[(1S,3R)-3-[[Terbutyl(dimethyl)decyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline 5-5-yl]-2-methyl-butan-2-ol (0.36 g, 0.95 mol) was dissolved in dichloromethane (9.5 mL). Diisopropylethylamine (499 μL, 2.86 mmol) was added. 2-(2-Chloro-5-methoxy-phenyl)acetic acid (229.5 mg, 1.14 mmol) was added. Add O- (7-aza-1H-benzotriazol-1-yl) -N,N,N',N' -tetramethyluronium hexafluorophosphate (561 mg, 1.40 mmol) at ambient temperature Stir overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 560.2 (M + 1).

The following compounds were basically prepared by the method of Preparation 25.

Preparation 28

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquinoline Synthesis of -2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one.

1-[(1S,3R)-5-bromo-3-({[T-butyl(dimethyl)decyl)oxy}methyl)-1-methyl-3,4-dihydroiso) Quinoline-2(1 H )-yl]-2-(2,6-dichlorophenyl)ethanone (300 mg, 0.54 mmol) and vinyl Dibutyl acrylate (0.24 mL, 1.08 mmol) was dissolved in 1,4-dioxin (5.4 mL). Aqueous Na ₂ CO ₃ (2.7 mL, 2 M in water) was added. Degassing with nitrogen for 10 min. Bis(triphenylphosphine)palladium(II) chloride (76 mg, 0.11 mmol) was added. Heat to 80 ° C. Stir for 2 hours. Water was added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 504 (M + 1).

Preparation 29

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-5-(1-hydroxyethyl)-1-methyl-3,4- Dihydroisoquinoline-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one (diastereomer Isomer mixture) and 1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl Synthesis of benzyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one.

1-((1S,3R)-3-(((Tertiarybutyldimethylalkyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquine Phenantholine-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one (477 mg, 0.95 mmol) was dissolved in THF (9.5 mL). Cool to 0 °C. Was added _{BH 3 (1.9mL, 1.89mmol, 1M} , in THF) is. Stir at room temperature for 4 h. Cool to 0 °C. Was added NaOH (3.8mL, 3M, stored in water) and _{H 2 O 2 (0.58mL, 30} % wt / wt%, stored in water). Stir at room temperature overnight. Ethyl acetate was added, washed with saturated NaHCO ₃ solution and brine, dried by sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane ( gradient: 5-60%) to give 1-((1S,3R)-3- (( Butyldimethylmethylalkyl)oxy)methyl)-5-(1-hydroxyethyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-yl)-2- (2,6-Dichlorophenyl)ethane-1-one (mixture of diastereomers) (92 mg, 0.19 mmol). MS (m/z): 522 (M+1); and 1-((1S,3R)-3-(((t-butyldimethyl)alkyl)oxy)methyl -5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane- 1-ketone (254 mg, 0.49 mmol). MS (m/z): 522 (M + 1).

Preparation 30

1-((1S,3R)-5-ethenyl-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-3,4-dihydroisoquine Synthesis of porphyrin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one.

1-((1S,3R)-3-(((Tertiarybutyldimethylalkyl)oxy)methyl)-5-(1-hydroxyethyl)-1-methyl-3,4 -Dihydroisoquinoline-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one (92 mg, 176 μmol, a mixture of two diastereomers) In CH ₂ Cl ₂ (1.8 mL). NaHCO ₃ (92 mg, 1.1 mmol) and 3,3,3-triethoxymethoxy-3-iodonium (90 mg, 211 μmol) were added at room temperature. Stir for 40 min. A saturated NaHCO ₃ solution and a saturated Na ₂ S ₂ O ₃ solution were added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 522 (M + 1).

The following compounds were prepared essentially by the method of Preparation 30.

Preparation 33

2-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-2-(2-(2,6-di) Synthesis of chlorophenyl)ethylidene)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acetaldehyde.

1-((1S,3R)-3-(((T-butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4 - dihydro-isoquinoline -2 (1H) - yl) -2- (2,6-dichlorophenyl) ethan-1-one (160mg, 0.31mmol) was dissolved (3.1 mL) in CH ₂ Cl ₂ . NaHCO ₃ (160 mg, 1.90 mmol) and 3,3,3-triethoxycarbonyl-3-iodonium (156 mg, 0.37 mmol) were added at room temperature. Stir for 40 min. A saturated NaHCO ₃ solution and a saturated Na ₂ S ₂ O ₃ solution were added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 520.2 (M + 1).

Preparation 34

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxypropyl)-1-methyl-3,4- Synthesis of dihydroisoquinoline-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one (a mixture of two diastereomers).

2-((1S,3R)-3-(((Tertiary butyldimethylmethylalkyl)oxy)methyl)-2-(2-(2,6-dichlorophenyl)ethenyl) 1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acetaldehyde (138 mg, 0.27 mmol) was dissolved in THF (2.7 mL). Was cooled to 0 ℃, was added MeMgCl (0.097mL, 0.29mmol, 3M, are stored in Et ₂ O). Stir at 0 ° C for 30 min. Water was added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 536.2 (M + 1).

The following compounds were prepared essentially by the method of Preparation 34.

Preparation 36

1-((1S,3R)-5-bromo-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinoline- Synthesis of 2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethane-1-one.

(1S,3R)-5-bromo-3-(((tert-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquine The porphyrin (1.85 g, 4.99 mmol) and 2-chloro-6-fluorophenylacetic acid (1.04 g, 5.49 mmol) were dissolved in dichloromethane (50 mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hydride (2.85 g, 7.49 mmol) and two were added at room temperature. different Propylethylamine (1.3 mL, 7.49 mmol). Stir for 3 hours. Water was added and extracted three times with dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 540.2 (M + 1).

Preparation 37

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquinoline Synthesis of -2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethane-1-one.

1-((1S,3R)-5-bromo-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinoline -2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethane-1-one (1.8 g, 3.33 mmol) and vinyl Dibutyl acrylate (1.5 mL, 6.65 mmol) was dissolved in 1,4-dioxin (22 mL). Aqueous Na ₂ CO ₃ (11 mL, 2M, taken in water) was added. Degassing with nitrogen for 10 min. Bis(triphenylphosphine)palladium(II) chloride (467 mg, 0.67 mmol) was added. Heat to 80 ° C. Stir for 2 hours. Water was added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 488.2 (M + 1).

Preparation 38

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4- Combination of dihydroisoquinoline-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethane-1-one to make.

1-((1S,3R)-3-(((Tertiarybutyldimethylalkyl)oxy)methyl)-1-methyl-5-vinyl-3,4-dihydroisoquine Phenantholine-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethane-1-one (1.54 g, 3.15 mmol) was dissolved in THF (31 mL). Cool to 0 °C. Was added _{BH 3 (6.3mL, 6.3mmol, 1M} , in THF) is. Stir at room temperature for 4 h. Cool to 0 °C. Was added NaOH (12.6mL, 3M, stored in water) and _{H 2 O 2 (1.92mL, 30} % wt / wt%, stored in water). Stir at room temperature overnight. Ethyl acetate was added, washed with saturated NaHCO ₃ solution and brine, dried by sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexane ( gradient: 5-60%) to give 1-((1S,3R)-3- (( Butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2- (2-Chloro-6-fluorophenyl)ethane-1-one (1.08 g, 2.13 mmol). MS (m/z): 506.2 (M + 1).

Preparation 39

2-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-2-(2-(2-chloro-6-fluorophenyl)ethenyl) Synthesis of 1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)acetaldehyde.

1-((1S,3R)-3-(((T-butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxyethyl)-1-methyl-3,4 - dihydro-isoquinoline -2 (1H) - yl) -2- (2-chloro-6-fluorophenyl) ethane-1-one (1.08g, 2.13mmol) was dissolved in CH ₂ Cl ₂ (21mL) in. NaHCO ₃ (1.08 g, 12.9 mmol) and 3,3,3-triethoxycarbonyl-3-iodonium (1.09 g, 2.56 mmol) were added at room temperature. Stir for 40 min. A saturated NaHCO ₃ solution and a saturated Na ₂ S ₂ O ₃ solution were added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj

Preparation 40

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline- Synthesis of 5-yl)propan-2-one.

Mixing (1S,3R)-5-bromo-3-(((tert-butyldimethylmethylalkyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquine Phytate hydrochloride (2.5 g, 6.14 mmol), acetone (30 mL), tripotassium phosphate N hydrate (3.99 g, 18.4 mmol), CataCXium A (bis(1-adamantyl)-n-butyl film, 220 mg, 0.61 mmol) and hydrazine (dibenzylideneacetone) dipalladium (0) (290 mg, 0.31 mmol). Stir at 70 ° C for 2 days. Cool to 0 °C. Water was added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 348 (M + 1).

Preparation 41

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-2-(2-(6-chloro-2-fluoro-3-methoxy) Phenyl)ethinyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)propan-2-one Synthesis.

1-((1S,3R)-3-(((Tertiary butyldimethylmethylalkyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline -5-yl)propan-2-one (1.3 g, 3.74 mmol) was dissolved in dichloromethane (37 mL). Diisopropylethylamine (2.0 mL, 11.22 mmol), 2-(6-chloro-2-fluoro-3-methoxyphenyl)acetic acid (1.06 g, 4.86 mmol), O. -(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.91 g, 4.86 mmol). Stir for 16 hours. Washed with saturated _aqueous NaHC03, by over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by EtOAc EtOAcjjjjjjj MS (m/z): 548.6 (M + 1).

Preparation 42

1-((1S,3R)-3-(((t-butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3 Synthesis of 4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one.

1-((1S,3R)-5-Ethyl-3-(((t-butyldimethyl)alkyl)oxy)methyl)-1-methyl-3,4-dihydroiso Quinoline-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one (68 mg, 130 [mu]mol) was dissolved in THF (1.3 mL). Cool to 0 ° C and add MeMgCl (87 μL, 261 μmol, 3M in Et ₂ O). Stir at 0 ° C for 30 min and at room temperature for 30 min. MeMgCl (87 μL, 261 μmol, 3 M, stored in Et ₂ O) was added at room temperature. Stir for 60 min. Water was added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with EtOAc EtOAcjjjjjjjj MS (m/z): 536.2 (M + 1).

The following compounds were prepared essentially by the procedure of Preparation 42.

Example 3

2-(2,6-Dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)ethane-1-one.

1-((1S,3R)-3-(((T-butyldimethylmethylalkyl)oxy)methyl)-5-(2-hydroxypropan-2-yl)-1-methyl- 3,4-Dihydroisoquinoline-2(1H)-yl)-2-(2,6-dichlorophenyl)ethane-1-one (0.054 g, 100 μmol) was dissolved in THF (1.0 mL) . Tetrabutylammonium fluoride (0.11 mL, 110 μmol, 1 M in THF) was added. Stir for 30 min. A saturated ammonium chloride solution was added and extracted three times with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered and evaporated The residue was purified by EtOAc EtOAc (EtOAc:EtOAc MS (m/z): 422 (M + 1).

Example 3a

Crystalline 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3 Preparation of 4-dihydroisoquinolin-2(1H)-yl)ethane-1-one.

1.932 g of 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl -3,4-Dihydroisoquinolin-2(1H)-yl)ethane-1-one was dissolved in cyclopentyl methyl ether at a concentration of 128 mg/mL while stirring at 80 ° C / 1000 rpm. The solution began to precipitate a white solid which was then cooled to ambient temperature after a short slurry period. The solid was separated by vacuum filtration and dried under nitrogen, and then dried in a vacuum oven at 65 ° C for 2 hours. 1.606 g of the title compound was recovered in a yield of 86.8%.

X-ray powder diffraction

The XRD pattern of the crystalline solid was obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa source (λ = 1.54060 Å) and a Vantec detector operating at 35 kV and 50 mA. The sample was scanned between 4° and 40° 2θ with a step size of 0.0087 ° 2θ and a scan rate of 0.5 sec/step, and a 0.6 mm divergence slit, 5.28 fixed anti-scatter slit And 9.5mm detector slits. The dry powder was stacked on a quartz sample holder and a smooth surface was obtained using a glass slide. It is well known in the art of crystallography that for any given crystal form, the relative intensities of the diffraction peaks can vary due to the preferred orientation resulting from factors such as crystal morphology and habit. In the presence of a better orientation, the peak intensity will change, but the characteristic peak position of the polymorph will not change. See, for example, U.S. Pharmacopoeia 35 - National Drug Set 30, Chapter <941> Characterization of crystalline and partially crystalline solids by X-ray powder diffraction (XRPD) official December 1, 2012 - May 1, 2013. In addition, it is also well known in the field of crystallography that the peak angular position may vary slightly for any given crystal form. For example, the peak position may be shifted due to changes in temperature or humidity at the time of analysis of the sample, displacement of the sample, or presence or absence of an internal standard. In this case, the peak position variability of ±0.2 2θ will take into account such potential changes, which does not prevent a clear identification of the specified crystal form. The confirmation of the crystal form can be carried out based on any unique combination of distinct peaks (usually more prominent peaks, in units of ° 2θ). The crystal form diffraction pattern collected at ambient temperature and relative humidity was adjusted at 8.85° and 26.77° 2θ based on the NIST 675 standard peak.

The prepared sample of the crystalline compound of Example 3a was characterized in that its X-ray diffraction pattern (using CuKa radiation) had a diffraction peak (2θ value) as set forth in Table 10 below. Specifically, the pattern contains a peak at 14.3 and contains one or more peaks selected from the group consisting of 15.7 peaks, 18.0 peaks, 18.7 peaks, 22.4 peaks, and 25.1 peaks, wherein the diffraction angle tolerance is 0.2 degrees.

The following compounds were essentially prepared by the method of Example 3.

Example 4a

Co-crystallized 2-(2,6-dichlorophenyl)-1-((1S,3R)-5-(2-hydroxy-2-methylpropyl)-3-(hydroxymethyl)-1-methyl Preparation of benzyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one and 4-hydroxybenzoic acid.

2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(2-hydroxy-2-methylpropyl)-3-(hydroxymethyl)-1-methyl -3,4-Dihydroisoquinolin-2(1H)-yl)ethane-1-one (98.33 mg) and 4-hydroxybenzoic acid (35.40 mg) were placed in a 20 mL vial equipped with a stir bar. The vial was filled with water (about 20 mL) and slurried overnight at 45 ° C (stirring plate setting). The sample was further slurried at 60 ° C for 48 hours and no crystal formation. Acetone (1 mL) was added and the sample was slurried overnight at 40 ° C / 1000 rpm. The material behaves as crystalline. The resulting white solid was isolated by vacuum filtration and dried in vacuo for 10 min.

X-ray powder diffraction

An X-ray diffraction (XRD) pattern of crystalline solids was obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa source (λ = 1.54060 Å) and a Vantec detector operating at 35 kV and 50 mA. The sample was scanned between 4° and 40° 2θ with a step size of 0.009° 2θ and a scan rate of 0.5 sec/step, and a 0.6 mm divergence slit, 5.28 fixed anti-scatter slit and 9.5 mm detector slit were used. . The dry powder was stacked on a quartz sample holder and a smooth surface was obtained using a glass slide. The crystal form diffraction pattern is collected at ambient temperature and relative humidity. It is well known in the art of crystallography that for any given crystal form, the relative intensities of the diffraction peaks can vary due to the preferred orientation resulting from factors such as crystal morphology and habit. In the presence of a better orientation, the peak intensity will change, but the characteristic peak position of the polymorph will not change. In addition, it is also well known in the field of crystallography that the peak angular position may vary slightly for any given crystal form. For example, the peak position may be shifted due to changes in temperature or humidity at the time of analysis of the sample, displacement of the sample, or presence or absence of an internal standard. In this case, the peak positional variability of 0.2 2θ will take into account such potential changes, which does not prevent a clear identification of the specified crystal form. The confirmation of the crystal form can be based on the difference The peak (usually a more prominent peak, in ° 2θ) is implemented in any unique combination. (US Pharmacopoeia 35, National Drug Collection No. 30, Chapter <941>, pp. 427-432, 2012). The crystalline form of the diffraction pattern collected at ambient temperature and relative humidity is adjusted according to the NIST standard reference material 675 (mica) having peaks at 8.85 and 26.77 degrees 22.

The prepared sample of the Example 4a eutectic is characterized in that its X-ray diffraction pattern (using CuKa radiation) has a diffraction peak (2θ value) as set forth in Table 11 below, and specifically has a 7.0 peak and one or more The peaks are selected from the group consisting of: 18.8 peaks, 16.1 peaks, and 19.3 peaks; wherein the diffraction angle tolerance is 0.2°.

Example 7

2-(2-Chloro-6-methoxy-phenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)- Synthesis of 1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone.

1-[(1S,3R)-3-[[Third butyl(dimethyl)decyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1- Methyl-3,4-dihydro-1H-isoquinolin-2-yl]-2-(2-chloro-6-methoxy-phenyl)ethanone (0.58 g, 1.04 mmol) was dissolved in THF ( 5.3mL). Acetic acid (16 mL, 279 mmol) and water (5.3 mL) were added. Stir at 50 ° C for 1.5 hours. Concentrate under reduced pressure. The residue was dissolved in ethyl acetate and washed with aq. Dry over sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc MS (m/z): 446.0 (M + 1).

The following compounds were essentially prepared by the method of Example 8.

Example 10

2-(2-Chlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3, Synthesis of 4-dihydro-1H-isoquinolin-2-yl]ethanone.

2-(2-Chlorophenyl)acetic acid (96.8 mg, 0.56 mmol) and O- (7-aza- 1H-benzotriazol-1-yl) -N , N , N ', N '-Tetramethylurea oxime (200 mg, 0.52 mmol) was dissolved in dichloromethane (2 mL). Diisopropylethylamine (183 μL, 1.05 mmol) was added. Allow to stand at ambient temperature for 20 min. The reaction mixture was added to 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoxyl in dichloromethane (0.4 mL). A solution of quinoline-5-yl]-2-methyl-butan-2-ol (92 mg, 0.35 mol). Rinse with dichloromethane (1 mL) and stir at ambient temperature for 3.5 h. The reaction mixture was diluted with water and stirred. Extracted with dichloromethane and dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc) The residue was purified by EtOAc EtOAc EtOAcjjjjj MS (m/z): 416.2 (M + 1).

The following compounds were prepared essentially by the method of Example 10.

Example 12

3-Chloro-2-[2-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-di Synthesis of hydrogen-1H-isoquinolin-2-yl]-2-oxo-ethyl]benzonitrile.

In a vial, 2-(2-chloro-6-cyano-phenyl)acetic acid (75.4 mg, 0.37 mmol) in acetonitrile (0.3 mL) was slurried. Triethylamine (114 μL, 0.82 mmol) was added and stirred until the solid dissolved. O- (benzotriazol-1-yl) -N , N , N ', N '-tetramethyluronium hydride (165 mg, 0.51 mmol) was added and stirred at ambient temperature for 10 min. In a separate flask, 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline in acetonitrile (0.3 mL) -5-yl]-2-methyl-butan-2-ol hydrochloride (102 mg, 0.34 mol) was slurried. Triethylamine (227 μL, 1.63 mmol) was added and a precipitate formed. Stir at ambient temperature for 10 min. 2-(2-Chloro-6-cyano-phenyl)acetic acid, acetonitrile, triethylamine and tetrafluoroboric acid O- (benzotriazol-1-yl) -N , N , N ', N '- The tetramethyluronium hydrazine reaction mixture was transferred from a vial to 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-5- A flask of a reaction mixture of 2-methyl-butan-2-ol hydrochloride, acetonitrile and triethylamine. Rinse with acetonitrile (0.9 mL) and stir the homogeneous reaction mixture at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, saturated sodium bicarbonate solution and brine. The extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc) The title compound (34 mg, 0.08 mmol): (m/z)

Preparation 46

Synthesis of 2-(2-chloro-6-methyl-phenyl)acetic acid.

To a 100 mL screw cap vial was added 2-(2-chloro-6-methyl-phenyl)acetonitrile (8.0 g, 48.30 mmol) and 3N aqueous sodium hydroxide (80 mL, 240.00 mmol). The mixture was heated at 110 ° C for 18 hr. The mixture was cooled to 10 ° C and acidified to pH 1 using concentrated hydrochloric acid (15 mL). The mixture was extracted with ethyl acetate. The organic phase was separated and dried over sodium sulfate. Filter and concentrate to dryness. Crystallization from diethyl ether to give the title in the form of an off-white solid Compound (7.20 g, 39.00 mmol): MS (m/z)

Preparation 47

Synthesis of tert-butyl 2-(2-chloro-5-isopropyl-phenyl)acetate.

To the round bottom flask was added bis(dibenzylideneacetone)palladium (49.2 mg, 85.6 μmol) and sealed using a septum. Rinse with nitrogen. Add tri-tert-butylphosphine (85.6 μL, 85.6 μmol, 1 M in toluene) and lithium bis(trimethyldecyl) guanamine (12.8 mL, 11.56 mmol, 0.9 M, in methyl) via syringe In cyclohexane). 2-Bromo-1-chloro-4-isopropyl-benzene (1.0 g, 4.28 mmol) and tert-butyl acetate (865.2 μL, 6.42 mmol) were added via syringe. Toluene (10.7 mL) was added via syringe and the reaction mixture became hot to the touch. Place in an ambient temperature water bath and stir for 3 hours. The reaction mixture was stored in a freezer during the weekend. The reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with diethyl ether and a saturated ammonium chloride solution was added. The layers were separated and the diethyl ether layer was washed with a saturated sodium chloride solution. Dry over sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjj Purification by EtOAc (EtOAc EtOAc (EtOAc) MS (m/z): 213.0 (M-tBu+1).

The following compounds were prepared essentially by the method of Preparation 47.

Preparation 49

Synthesis of 2-(2-chloro-5-isopropyl-phenyl)acetic acid.

2-(2-Chloro-5-isopropyl-phenyl)acetic acid tert-butyl ester (483 mg, 1.80 mmol) was dissolved in dichloromethane (5.1 mL). Trifluoroacetic acid (1.09 mL, 14.4 mmol) was slowly added and the mixture was stirred at ambient temperature for 3 h. Concentration under reduced pressure gave the title compound (380 mg, 1. MS (m/z): 229.8 (M+18).

The following compounds were prepared essentially by the method of Preparation 49.

Preparation 51

Synthesis of 2-(3-isopropoxyphenyl)acetic acid isopropyl ester.

2-(3-Hydroxyphenyl)acetic acid (5.04 g, 32.8 mmol) was dissolved in dimethylformamide (49.9 mL). Potassium carbonate (15.1 g, 108.2 mmol) and 2-iodopropane (15.1 mL, 150.8 mmol) were added. The reaction mixture was heated to 80 ° C for 6 hours. Stir at ambient temperature for 64 hours. The reaction mixture was heated to 95 ° C for 6 hours.

Additional potassium carbonate (9.2 g, 65.6 mmol) and 2-iodopropane (15.1 mL, 150.8 mmol) were added and the mixture was warmed to <RTIgt; Raise the temperature of the reaction mixture to Heat at 150 ° C overnight. Cool to ambient temperature and concentrate under reduced pressure. The residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, dried over sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 237.0 (M+H), 254.0 (M+18).

The following compounds were basically prepared by the method of Preparation 51.

Preparation 53

Synthesis of 2-(3-isopropoxyphenyl)acetic acid.

2-(3-Isopropoxyphenyl)acetic acid isopropyl ester (4.2 g, 17.8 mmol) was dissolved in tetrahydrofuran (35.6 mL). Water (35.6 mL) and lithium hydroxide (6.05 g, 248.8 mmol) were added. The reaction mixture was heated to 66 °C overnight. Concentration under reduced pressure to remove tetrahydrofuran. The reaction mixture was diluted with water and washed with diethyl ether. The aqueous layer was acidified to pH 1 using 5N HCl. The aqueous layer was extracted with diethyl ether. The diethyl ether extract was washed with water and brine, dried over sodium sulfate. MS (m/z): 195.0 (M + 1), 212.0 (M + 18).

The following compounds were prepared essentially by the procedure of Preparation 53.

Preparation 55

Synthesis of 2-(2-chloro-5-isopropoxy-phenyl)acetic acid.

2-(3-Isopropoxyphenyl)acetic acid (3.24 g, 16.6 mmol) was dissolved in dimethylformamide (11.1 mL). It was cooled in an ice bath and a solution of N-chlorosuccinimide (2.44 g, 18.3 mmol) in dimethylformamide (12.2 mL) was added. Stir overnight to bring the reaction solution to ambient temperature. The reaction mixture was diluted with diethyl ether. Wash with water. The water wash was extracted with diethyl ether. The combined diethyl ether extracts were washed with water and brine, dried over sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjj MS (m/z): 245.8 (M+18).

The following compounds were prepared essentially by the procedure of Preparation 55.

Preparation 57

Synthesis of methyl 2-(2-chloro-6-cyano-phenyl)acetic acid.

A 2 M solution of lithium diisopropylguanamine (62.6 mL, 461.8 mmol) in tetrahydrofuran was added to tetrahydrofuran (1 L) at -78. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (19.94 mL, 164.91 mmol) was slowly added, followed by dropwise addition of 3-chloro-2-methyl-benzene Formonitrile (20 g, 131.93 mmol). The mixture was maintained at -78 °C and stirred for 5 min. The reaction vessel was purged with carbon dioxide (1 L; 25.65 moles) for 15 min. Water (100 mL) was added and stirred for 2 hr. A 10 M aqueous sodium hydroxide solution was added to increase the pH of the aqueous phase to >12. The aqueous layer was separated and washed with diethyl ether. The aqueous layer was acidified to pH-1 using concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was separated and dried over sodium sulfate. Filtration and concentrating to dryness to give the title compound (16.0 g; 81. MS (m/z): 195.9 (M + 1).

Preparation 58

(1S,3R)-3-[[T-butyl(dimethyl)decyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid Synthesis of methyl esters.

(1S,3R)-5-bromo-3-((t-butyldimethylmethylalkyloxy)methyl)-1-methyl-1,2 in a glass pressure vessel containing a magnetic stir bar , 3,4-tetrahydroisoquinoline (30 g, 81.0 mmol), palladium acetate (1.8 g, 8.1 mmol), bis-(1,3-diphenylphosphino)propane (6.7 g, 16.2 mmol) and carbonic acid Sodium (34.3 g, 324.0 mmol) was suspended in a mixture of dimethylhydrazine (360 mL) and methanol (180 mL). The vessel was filled with carbon monoxide (410 kPa) and heated to 100 ° C with stirring. The temperature was maintained at 100 ° C for 19 hours. The mixture was cooled to ambient temperature. The resulting suspension was filtered and diluted with methyl tert-butyl ether (1000 mL) liquid. The solution was washed with brine (3 x 500 mL). The title compound (26.7 g, 76.4 mmol): m.

Preparation 59

(1S,3R)-3-[[t-butyl(dimethyl)decyl]oxymethyl]-2-[2-(6-chloro-2-fluoro-3-methoxy-phenyl) Synthesis of methyl ethyl hydrazide]-1-methyl-3,4-dihydro-1H-isoquinoline-5-carboxylate.

Addition of triethylamine (0.36 mL, 2.57 mmol) to (1S,3R)-3-[[T-butyl(dimethyl)decyl]oxyl in dimethylformamide (6.4 mL) Methyl methyl-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid methyl ester (500 mg, 1.29 mmol), hexafluorophosphoric acid (benzotriazol-1-yloxy) A stirred solution of tripyrrolidinylhydrazine (1.02 g, 1.93 mmol) and 2-(6-chloro-2-fluoro-3-methoxy-phenyl)acetic acid (356 mg, 1.54 mmol). Stir at room temperature for 16 h. A saturated aqueous solution of ammonium chloride (60 mL) was added. Extract with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine. Dry over magnesium sulfate, filter and concentrate under reduced pressure. The title compound (703 mg, 1.15 mmol): m.

The following compounds were prepared essentially by the method of Preparation 59.

Example 13

2-(6-Chloro-2-fluoro-3-methoxy-phenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl- Synthesis of ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone.

A 0.6 M solution of ruthenium (III) bis(lithium chloride) complex in tetrahydrofuran (1.92 mL, 1.15 mmol) was added to (1S,3R)-3-[ [Third butyl(dimethyl)decyl]oxymethyl]-2-[2-(6-chloro-2-fluoro-3-methoxy-phenyl)ethenyl]-1-methyl A stirred solution of methyl 3-,4-dihydro-1H-isoquinoline-5-carboxylate (703 mg, 1.15 mmol). Stir at room temperature for 40 minutes. A 3 M solution of methylmagnesium bromide (3.50 equivalent; 4.03 mmol; 1.34 mL; 1.39 g) in diethyl ether was added dropwise. The reaction mixture was stirred for 1.5 h. It was quenched with brine (25 mL). After the gas evolution ceased, it was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine. Dry over magnesium sulfate, filter and concentrate under reduced pressure. The residue was redissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride trihydrate (492 mg, 1.73 m). Stir at room temperature for 2 h. Concentrate under reduced pressure. The residue was washed with a short flash of EtOAc (EtOAc) (EtOAc). Concentrate under reduced pressure. The title compound (349 mg, 0.76 mmol): (m/z)

The following compounds were essentially prepared by the method of Example 13.

Claims (16)

a compound of the formula Wherein n is 0, 1 or 2; R ¹ is halogen; R ² is halogen, H, CN, C1-C3 alkoxy or C1-C3 alkyl; and R ³ is H, halogen, C1-C3 alkoxy Or a C1-C3 alkyl group. The compound of claim 1, which has the formula: Wherein n is 0, 1 or 2; R ¹ is halogen; R ² is halogen, H, CN, C1-C3 alkoxy or C1-C3 alkyl; and R ³ is H, halogen, C1-C3 alkoxy Or a C1-C3 alkyl group. The compound of claim 1 or 2, wherein: n is 0, 1 or 2; R ¹ is halogen; R ² is halogen; and R ³ is hydrogen or C1-C3 alkoxy. The compound of claim 1 or 2, wherein: n is 0, 1 or 2; R ¹ is Cl, F or Br; R ² is Cl, OCH ₃ , H, F, CN or CH ₃ ; and R ³ is OCH ₃ , H, CH ₂ CH ₃ , Cl, OCH(CH ₃ ) ₂ , OCH ₂ CH ₃ , F, CH(CH ₃ ) ₂ or CH ₃ . The compound of any one of claims 1, 2 or 3, wherein: n is 0 or 2; R ¹ is Cl; R ² is Cl or F; and R ³ is H or OCH ₃ . The compound of claim 1, which is 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methyl Butyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone. A composition comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl) 1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid. A co-crystallized form of the composition of claim 7. The co-crystallized form of the composition of claim 8, wherein the X-ray powder diffraction pattern using CuKα radiation has a diffraction peak at a 18.2° 2θ diffraction angle and has one or more peaks selected from the group consisting of: 16.0°, 25.4°, and 7.0°; wherein the diffraction angle has a tolerance of 0.2°. A pharmaceutical composition comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl -1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl]ethanone and 4-hydroxybenzoic acid together with a pharmaceutically acceptable carrier, diluent or excipient. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier, diluent or excipient. A method of treating Parkinson&apos;s disease comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 6. A method of treating schizophrenia comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 6. A compound according to any one of claims 1 to 6 for use in therapy. A compound according to any one of claims 1 to 6 for use in the treatment of Parkinson's disease. A compound according to any one of claims 1 to 6 for use in the treatment of schizophrenia.